This invention relates to compositions and methods for preventing miscarriage and premature labor, and for treating and preventing Bacterial Vaginosis.
Bacterial Vaginosis (BV) is broadly defined as a shift in vaginal ecology from a normal lactobacillus dominated flora to a profuse mixed microbial flora consisting of facultative and anaerobic organisms. An ancient condition first described by Hippocrates, BV is now the most common vaginal disorder in women of reproductive age, Kent, H. L., Epidemiology of vaginitis, A. J Obstet. Gynecol. 1991 165:1168, afflicting 15 to 20 percent of all women at any given time. In the United States, BV is the leading variety of vaginal infection, affecting a broader spectrum of women than gonorrhea. Id.
A primary medical significance of BV is its impact upon the quality of fetal implantation and its potential to induce premature labor, resulting in low birth-weight infants. BV during pregnancy also has been associated with an increased risk of late miscarriage. Kurki, T, et al., Bacterial vaginosis in early pregnancy and pregnancy outcome, Obstet. Gynecol. 1992, 80:173-77; Riduan, J. M. et al., Bacterial vaginosis and prematurity in Indonesia: Association in early and late pregnancy, Am. J. Obstet. Gynecol. 1993, 169:175-78; Hay, P. E., et al., Abnormal bacterial colonization of the genital tract and subsequent preterm delivery and late miscarriage, BMJ 1994, 308:295-98; McGregor, J. A., et al., Prevention of premature birth by screening and treatment for common genital tract infections results of a prospective controlled evaluation, Am J. Obstet. Gynecol. 1995, 173:157-67, Hillier, S. L., et al., Association between bacterial vaginosis and preterm delivery of a low birth-weight infant, N. Engl. J. Med. 1995, 333,1737-42; Watts, D. H., et al., Bacterial vaginosis as a risk factorforpost-cesarean endometriosis, Obstet. Gynecol. 1990, 75,52-58.
The prevalence of BV in pregnant women is reported to be about 13 to 31 percent. Kurki, T, et al., Bacterial vaginosis in early pregnancy and pregnancy outcome, Obstet. Gynecol. 1992, 80,173-77. Riduan, J. M. et al., Bacterial vaginosis and prematurity in Indonesia: Association in early and late pregnancy, Am. J. Obstet. Gynecol. 1993, 169:175-78; Hay, P. E., et al., Abnormal bacterial colonization of the genital tract and subsequent preterm delivery and late miscarriage, BMJ 1994, 308:295-98; McGregor, J. A., et al., Prevention of premature birth by screening and treatment for common genital tract infections: results of a prospective controlled evaluation, Am J. Obstet. Gynecol. 1995, 173:157-67; Hillier, S. L., et al., Association between bacterial vaginosis and preterm delivery of a low birth-weight infant, N. Engl. J. Med. 1995, 333:1737-42. In women undergoing in-vitro fertilization, BV is associated with increased risk of miscarriage in the first trimester. Ralph, S. G. et al., Influence of bacterial vaginosis on conception and miscarriage in the first trimester. Cohort study, BMJ 1999, 319,220-3. Even if the fetus of a woman suffering from BV does survive the first and second trimester, however, the mother still faces an increased risk of premature labor with a higher probability of a low birthweight infant and the attendant problems and consequences.
The exact pathogenesis and medical classification (e.g., disease or condition) of BV is uncertain. Under normal conditions, lactobacillus bacteria are predominant in the vagina and are believed to regulate the growth of other vaginal flora by producing hydrogen peroxide (H2O2). In women with BV, however, normal vaginal lactobacilli are replaced by an overgrowth of Gardnerella vaginalis, anaerobes, and mycoplasmas, with a concomitant decrease in lactobacilli. Thus, while H2O2-producing lactobacilli can be found in women with BV, these may not be enough to overcome the onslaught of multiplying endogenous bacteria that in turn force out lactobacilli as the dominant member of the flora. Rosenstein, I. J., et al, Relationship between hydrogen peroxide producing strains of lactobacilli and vaginosis associated with bacterial species in pregnant women, Eur. J. Clin. Microbial. Infect. Dis. 1997, 6:517-22.
The diagnostic signs of BV include increased vaginal discharge, production of xe2x80x9cfishyxe2x80x9d smelling amines, vaginal pH above 4.7, and presence of clue cells within a mixed flora. These were first described by Gardner and Dukes in 1955, Gardner H. L., Dukes, D. C., Haemophilus vaginalis vaginitis. A newly defined specific infection previously classified xe2x80x9cnonspecific vaginitis, Am. J. Obstet. Gynecol. 1955, 69:962-76, and defined as the basic diagnostic criteria for BV in 1983. Amsel, R., et al., Nonspecific Vaginitis. Diagnostic criteria and microbial and epidemiologic associations, Am. J. Med. 1983, 74:14-22.
A woman may or may not experience the symptoms of BV; many women, however, complain of foul, fishy odor and excessive vaginal discharge that stains undergarments. The odor is particularly prominent for 24 hours after unprotected intercourse because of the high pH (7.8-8.2) and extensive buffering capacity of semen. Women who have recently acquired BV may be more aware of abnormal odor and discharge than a woman who has had the problem for months or even years. Often women first recognize that they had a problem after appropriate therapy. Further, many healthy women consider the symptoms of BV to indicate a lack of proper hygiene, rather than a medical problem.
In the United States, the unpleasant odor and discharge associated with BV causes many women to seek diagnosis and cure, which can be both inconvenient and costly. While millions seek the help of a physician for such problems, an even larger number (approximately 30% of all adult American women) often use douches purchased without a prescription, rather than seek medical advice.
The idea of washing out the foul smelling discharge with an acidic douche may have a simplistic appeal. Medically, however, douching is frowned upon as studies have demonstrated an association between douching and Pelvic Inflammatory Disease (PID), ectopic pregnancy, tubal infertility, and reduced fertility. Aral, S. O., et at., Self-reported pelvic inflammatory disease in the United States, 1988, JAMA 1991, 266:2570-3; Wolner-Hansen, P., et al., Association between vaginal douching and acute pelvic inflammatory disease, JAMA 1990, 263:1936-41; Scholes, D., et al., Vaginal douching as a risk factor for acute pelvic inflammatory disease, Obstet. Gynecol. 1993, 81:601-6; Chow, W-H, et al., Vaginal douching as a riskfactor for tubal ectopic pregnancy, Am. J. Obstet. 1985, 153:727-9; Chow, J. M., et al., The association between Chlamydia trachomatis and ectopic pregnancy, JAMA 1990, 263:3164-7; Darling J. R., et al., Vaginal douching and the risk of tubal pregnancy, Epidemiology 1991, 2:40-8; Kendrick, J. S., et al., Vaginal douching and the risk of ectopic pregnancy among black women, Am. J. Obstet. Gynecol. 1997, 176:991-7; Baird, D. D., et al., Vaginal Douching and reduced fertility, Am. J Public Health 1996, 86:844-50.
Traditional treatments of BV have focused on long-term cure. Treatment with the classic agents metronidazole and clindamycin have resulted in an approximately 70 percent cure rate within one month. Amsel, R., et al., Nonspecific vaginitis. Diagnostic criteria and microbial and epidemiologic associations, Am. J. Med 1983, 74:14-22; Larsson, P. G., Treatment for bacterial vaginosis: an update on the expected cure rate, Int""l J. of STD and AIDS 1997, 8:35-6. Nevertheless, only half of the women treated successfully will have a long-term cure. Larsson, P. G., et al., Treatment of bacterial vaginosis in women with vaginal bleeding complications or discharge or harboring Mobiluncus, Obstet. Gynecol. 1990, 29:296-300. Most relapses occur in the first year, often correlating to the introduction of a new sexual partner. Id. Thus, control of chronic BV is of primary importance to those who must deal with the problem.
The present invention relates to a pharmaceutical composition for preventing premature labor comprising a therapeutically-effective amount of aqueous pH-buffering bioadhesive water-insoluble but water-swellable cross-linked polycarboxylic acid polymer.
The present invention also relates to a pharmaceutical composition for preventing miscarriage comprising a therapeutically-effective amount of aqueous pH-buffering bioadhesive water-insoluble but water-swellable cross-linked polycarboxylic acid polymer.
The present invention also relates to a pharmaceutical composition for treating or preventing Bacterial Vaginosis comprising a therapeutically-effective amount of aqueous pH-buffering bioadhesive water-insoluble but water-swellable cross-linked polycarboxylic acid polymer.
The present invention further relates to a method of preventing premature labor, comprising administering a composition containing a therapeutically effective amount of an aqueous pH-buffering bioadhesive water-insoluble but water-swellable cross-linked polycarboxylic acid polymer to the vagina of a patient in need thereof.
The present invention further relates to a method of preventing miscarriage, comprising administering a composition containing a therapeutically effective amount of an aqueous pH-buffering bioadhesive water-insoluble but water-swellable cross-linked polycarboxylic acid polymer to the vagina of a patient in need thereof.
The present invention also relates to a method of treating or preventing Bacterial Vaginosis, comprising administering a composition containing a therapeutically effective amount of an aqueous pH-buffering bioadhesive water-insoluble but water-swellable cross-linked polycarboxylic acid polymer to the vagina of a patient in need thereof.
Definitions
xe2x80x9cTreating or preventing Bacterial Vaginosisxe2x80x9d refers to:
(i) preventing Bacterial Vaginosis in females that may be predisposed to bacterial vaginosis;
(ii) inhibiting Bacterial Vaginosis, i.e., arresting its development; and/or
(iii) relieving Bacterial Vaginosis, i.e., causing its regression or the regression of symptoms associated with bacteria vaginosis.
xe2x80x9cPreventing miscarriagexe2x80x9d includes, without limitation, eliminating miscarriage, or reducing the incidences of miscarriage in women by treating or preventing Bacterial Vaginosis, whether or not the symptoms of Bacterial Vaginosis are manifest in the patient.
xe2x80x9cPreventing premature laborxe2x80x9d includes, without limitation, eliminating premature labor, or reducing the incidences of premature labor in women by treating or preventing Bacterial Vaginosis, whether or not the symptoms of Bacterial Vaginosis are manifest in the patient.
xe2x80x9cTherapeutically effective amountxe2x80x9d refers to the amount required to produce the desired medical result.
xe2x80x9cPatientxe2x80x9d refers to a person who is under medical care or treatment.
Pharmaceutical Composition of the Present Invention
The water-swellable but water-insoluble cross-linked bioadhesive polycarboxylic acid polymer formulation used in the present invention is generally described in U.S. Pat. No. 4,615,697 to Robinson (hereinafter xe2x80x9cthe ""697 patentxe2x80x9d), which is incorporated herein by reference. At least eighty percent of the monomers of which the polymer is comprised should contain at least one carboxyl functionality. The cross-linking agent must be present at such an amount as to provide sufficient bioadhesion and water insolubility. These characteristics allow the system to remain attached to the target epithelial surfaces for a sufficient time to effectively reduce the vaginal pH level. Generally, the polymer should be present in the formulation at about 0.5 to about 5 percent by weight, although as much as 8 percent by weight is acceptable. Preferably, the polymer is present in the invention at about 2 percent by weight.
A sufficient level of bioadhesion is usually attained when the cross-linking agent is present at about 0.1 to 6.0 weight percent of the polymer. More preferably, the cross-linking agent is present at about 1.0 to 2.0 weight percent of the polymer. Suitable cross-linking agents include, among others, divinyl glycol, divinylbenzene, N,N-diallylacrylamide, 3,4-dihydroxy-1,5-hexadiene, 2,5-dimethyl-1,5-hexadiene, and other similar agents. Adhesive strengths may be measured by commercially available surface tensiometers.
A preferred polymer for use herein is Polycarbophil. Polycarbophil U.S.P. is commercially available from B. F. Goodrich Specialty Polymers of Cleveland, OH, under the trade name NOVEON(copyright)-AA1. Polycarbophil is a polyacrylic acid that is cross-linked with divinyl glycol. The United States Pharmacopeia; 1995 edition, United States Pharmacopeial Convention, Inc., Rockville, Md., at pages 1240-41.
The instant polymer, and Polycarbophil in particular, has been used in a variety of drug delivery systems. The polymer formulation in the ""697 patent is disclosed therein for use generally in a controlled release treatment composition, for providing controlled release of a separate treating agent. Specifically, the polymer has been disclosed for use in a controlled release composition with fluorometholone (U.S. Pat. No. 4,795,436) and with ophthalmic treatment compositions generally (U.S. Pats. Nos. 4,983,392 and 5,225,196). It has also been used in compositions to deliver other active treating agents, including, for example, progesterone (Crinone(copyright)) (see U.S. Pat. No. 5,543,150), Nonoxynol-9 (Advantage-S(copyright)) (see U.S. Pat. No. 5,667,492), and xcex2-adrenergic agonists (see U.S. Pat. No. 6,126,959).
The polymer, and specifically Polycarbophil, is itself the active ingredient in the vaginal moisturizer Replens(copyright) (see U.S. Pat. No. 5,474,768 (vaginal moisturization). U.S. Pat. No. 5,968,500 also discloses use of the polymer for general epithelial tissue moisturization.
Use of the polymer to control vaginal pH to alleviate microorganism growth and feminine odor such as presented by bacterial vaginosis is disclosed in U.S. Pat. No. 6,017,521.
Other useful bioadhesive polymers that may be used in the inventive method are mentioned in the ""697 patent. For example, these include polyacrylic acid polymers cross-linked with 3,4-dihydroxy-1,5-hexadiene, and polymethacrylic acid polymers cross-linked with divinyl benzene.
These polymers should not be used in their salt form because this would decrease their bioadhesive capability. These bioadhesive polymers may be prepared by conventional free radical polymerization techniques known to a skilled artisan, i.e., by utilizing initiators such as benzoyl peroxide and azobisisobutyronitrile. Exemplary methods of preparing useful bioadhesives are also disclosed in the ""697 patent.
Additionally, any one or more of the additives or adjuvants taught in the ""697 patent may be mixed in with the cross-linked polymer in the formulation for maximum efficacy of the pH buffering system or for the comfort of the patient. Such additives or adjuvants may include, among others, lubricants, plasticizing agents, preservatives, gel formers, tablet formers, pill formers, suppository formers, film formers, cream formers, disintegrating agents, coatings, binders, vehicles, coloring agents, taste controlling agents, odor controlling agents, humectants, viscosity controlling agents, and pH-adjusting agents. The present invention contemplates other additives known to an ordinarily skilled artisan.
The bioadhesive formulation may be in the form of a gel, cream, tablet, pill, capsule, suppository, film, or any other pharmaceutically acceptable form that adheres to the mucosa and does not wash away easily.
A preferred embodiment of the inventive composition comprises the following ingredients:
The individual ingredients of the preferred embodiment in Table 1 are well known and readily available from suppliers known in the industry.
Glycerin is a humectant. Alternative humectants include, for example, propylene glycol and dipropylene glycol.
Carbomer 934P is a gel former, which may be substituted by other gel formers including, but not limited to, carbomer 974, carbomer 980, methylcellulose or propylcellulose.
Ethylmethylpropylparaben is a preservative, which may be substituted by any other known preservative, such as benzoic acid or propionic acid.
The preferred embodiment of Table 1 may be generally prepared as follows. The ethylmethylpropylparaben (NIPASEPT(copyright), Nipa Laboratories Ltd.) is completely dissolved in the purified water. The glycerin is then added to the water phase. After the glycerin is completely dissolved in the water phase, the polycarbophil ((NOVEON AA1(copyright), B.F. Goodrich Specialty Polymers) and Carbomer 934P (CARBOPOL(copyright) 974P, B. F. Goodrich Chemical Co.) are added by very slowly vortex of the blender. The composition is mixed until the polymers have fully dispersed and the mixture is thoroughly homogenized. A vacuum of approximately xe2x88x920.3 bar is then applied and the mixture is left for 20 minutes to allow for deaeration while mixing. The result is a uniform, creamy white product with a pH generally of about 3.
As will be apparent to those skilled in the art, the composition can be varied to affect certain properties of the formulation. For example, the concentration of the bioadhesive polymer can be adjusted to provide greater or lesser bioadhesion. The viscosity can also be varied by varying the pH or by changing the concentration of the polymer or gel former.
A second preferred embodiment of the inventive composition comprises the following ingredients:
The individual ingredients of the preferred embodiment in Table 2 are well known and readily available from suppliers known in the industry.
Glycerin is a humectant. Alternative humectants include, for example, propylene glycol and dipropylene glycol.
Carbomer 934P is a gel former, which may be substituted by other gel formers including, but not limited to, Carbomer 974, Carbomer 980, methylcellulose or propylcellulose.
Mineral oil and hydrogenated palm oil glyceride are lubricating agents. Alternatives include, for example, any mineral oil or vegetable oil, such canola oil, palm oil or light mineral oil.
Sorbic acid is a preservative, which may be substituted by any other known preservative, such as benzoic acid or propionic acid.
General preparation involves hydration of the polymers, separate mixing of the polymer phase (water-soluble ingredients) and the oil phase (oil-soluble ingredients), heating and mixing of the two phases, and homogenization of the mixture. As an example, the polymer phase may be prepared by dissolving sorbic acid in purified water (which should contain approximately 3% of excess volume to account for evaporative losses), preferably at 75xc2x0-78xc2x0 C. The mixture is then cooled generally to room temperature, and the polycarbophil and Carbomer 934P are added to the mixture. The polymers are hydrated by mixing for several hours, generally about 2-3 hours until a uniform, smooth, homogenous, lump-free, gel-like polymer mixture is obtained.
The oil phase is generally prepared by melting together the hydrogenated palm oil glyceride, glycerin, and mineral oil. The mixture is then cooled to about 60xc2x0 C. The polymer phase, described above, is meanwhile warmed to about the same temperature. The polymer phase is then added to the heated oil phase. The two phases are mixed thoroughly, producing a uniform, creamy white product with a pH generally of about 3. When the mixture is cooled, it is de-aerated.
As will be apparent to those skilled in the art, the composition can be varied to affect certain properties of the formulation. For example, the concentration of the bioadhesive polymer can be adjusted to provide greater or lesser bioadhesion. The viscosity can also be varied by varying the pH or by changing the concentration of the polymer or gel former.
Methods of the Present Invention
The present inventive relates to methods and compositions for preventing miscarriage and premature labor and for treating or preventing Bacterial Vaginosis, comprising inclusion or use of a therapeutically effective amount of an aqueous pH-buffering bioadhesive water-insoluble but water-swellable cross-linked polycarboxylic polymer for vagina administration, thereby reducing vaginal pH for an extended period of time.
It is possible to reliably reduce vaginal pH for an extended period of time using a weak poly-acid containing multiple carboxyl radicals that are the source of its negative charges. These acid radicals permit hydrogen bonding with the cell surface. Although hydrogen bonds are weak, they are numerous and therefore tenacious. Robinson, J. R., Leung S-H, Park, H., Mechanisms of adhesion of swelling insoluble polymers to mucin epithelial surfaces, Proceedings of the 12th International Symposium on Controlled Release of Bioactive Materials, 12 (1985); Park, H., Rovinso, J. R., Physico-chemical properties of water insoluble polymers important to mucinlepithelial adhesion, J. of Controlled Release 2, 47-57 (1985). Thus, the bioadhesive polymers stay attached to the vaginal epithelial cells until they turn-over, normally up to 3 to 5 days. Id., March, D., Nakamura, R., Evaluation of the duration of effect of a bioadhesive vaginal moisturizing gel on vaginal pH, Abstract presented at the 7th International Congress on the Menopause, Jun. 20-24, 1993, Stockholm, Sweden. Since the polymers are weak poly-acids with exceedingly high buffering capacity, they maintain the vaginal pH in the physiologic range of less than 5 and thus help protect against infection. Id. This effect has been shown to persist for more than 96 hours. Id. Polycarbophil, as an example, has a pKa of 4.3 and, as with all good buffers, it will adjust the pH of the environment close to its pKa. Vaginal douches, on the other hand, have only a transient effect upon vaginal pH and cannot maintain a physiologic pH.
Preferably the inventive formulation remains attached to the epithelial surfaces for a period of at least 24 to 48 hours. Such results may be measured clinically over various periods of time, by testing samples from the vagina for pH reduction due to the continued presence of the polymer.
The rationale for using a vaginal preparation containing such a bioadhesive polymer is its ability to maintain vaginal pH in the physiologic range, thereby preventing the volatilization of amines, favoring the restoration of acidophilic lactobacilli as the dominant member of the flora, and making the environment hostile to a profuse mixed facultative and anaerobic microbial flora.